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Volume 21, Issue 4
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Introduction

With a projected mortality toll of 1.4 million in 2019, tuberculosis (TB) continues to be a significant public health concern around the world. Studies of novel treatments are required due to decreased bioavailability, increased toxicity, increased side effects, and resistance of several first- and second-line TB therapies, including isoniazid and ethionamide.

Methods

This study reports the synthesis of oxindole-based hybrids as potent InhA inhibitors targeting . The synthesized compounds (- and -) were evaluated for their anti-mycobacterial activity against and nontuberculous mycobacteria (NTMs), (ATCC 19977), (ATCC 6841), and (ATCC 35752) using the Microplate Alamar Blue Assay (MABA). Molecular docking studies were performed using AutoDock Vina to explore the binding interactions of these compounds with the InhA enzyme (PDB: 2NSD). Additionally, biochemical and histopathological studies were conducted to assess the hepatotoxicity of the lead compounds. molecular properties and ADMET properties of the synthesized compounds were predicted using SwissADME and Deep-PK online tools to assess their drug-likeness.

Results

Among the tested compounds, exhibited significant anti-mycobacterial activity with a minimum inhibitory concentration (MIC = 1 μg/mL) comparable to the reference drug ethambutol. Further, the compound demonstrated a binding affinity and orientation similar to the reference inhibitor 4PI, indicating its potential as a potent InhA inhibitor, and was found to be stabilized within the binding pocket of InhA through H-bonding, hydrophobic and van der Waal’s interactions. Besides, the compounds hepatotoxicity assessment studies depicted that showed no significant liver dysfunction or damage to liver tissues. Additionally, adhered to Lipinski’s rule of five and Veber’s rule, displaying favourable pharmacokinetic and drug-like properties, including high human intestinal absorption, distribution, and acceptable metabolic stability and excretion.

Conclusion

Compound emerged as a promising candidate for further optimization and development as a therapeutic agent for tuberculosis, offering a new avenue for tackling tuberculosis.

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2024-10-31
2025-06-21

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Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction of Oxindole-based Hybrids for the Treatment of Tuberculosis
Curr. Computeraided Drug Des. 21, 517 (2025); https://doi.org/10.2174/0115734099353857241022102426
/content/journals/cad/10.2174/0115734099353857241022102426
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  • Article Type:     Research Article
Keyword(s): ADMET; hepatotoxicity studies; InhA inhibitors; molecular docking; oxindole-based hybrids; Tuberculosis

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